Hypolipidemic benzothiazepines

ABSTRACT

The invention is concerned with novel hypolipidemic compounds of formula (I), with processes and novel intermediates for their preparation, pharmaceutical compositions containing them and with their use in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions, and associated diseases such as atherosclerosis. ##STR1##

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/GB95/02700 filed Nov. 16, 1995 which claims priority fromGB9423172.7 filed Nov. 17, 1994.

The present invention is concerned with new hypolipidemic compounds,with processes and novel intermediates for their preparation, withpharmaceutical compositions containing them and with their use inmedicine, particularly in the prophylaxis and treatment ofhyperlipidemic conditions and associated conditions such asatherosclerosis.

Hyperlipidemic conditions are often associated with elevated plasmaconcentrations of low density lipoprotein (LDL) cholesterol. Suchconcentrations can be reduced by decreasing the absorption of bile acidsfrom the intestine. One method by which this may be achieved is toinhibit the bile acid active uptake system in the terminal ileum. Suchinhibition stimulates the conversion of cholesterol to bile acid by theliver and the resulting increase in demand for cholesterol produces acorresponding increase in the rate of clearance of LDL cholesterol fromthe blood plasma or serum.

A novel class of heterocyclic compounds has been identified which reducethe plasma or serum concentrations of LDL cholesterol and in consequenceare particularly useful as hypolipidemic agents. By decreasing theconcentrations of cholesterol and cholesterol ester in the plasma, thecompounds of the present invention retard the build-up ofatherosclerotic lesions and reduce the incidence of coronary heartdisease-related events. The latter are defined as cardiac eventsassociated with increased concentrations of cholesterol and cholesterolester in the plasma or serum.

International Patent Application No. WO 93/16055 describes1,4-benzothiazepine compounds which have hypolipidemic activity. A groupof novel substituted 1,5-benzothiazepine compounds has now beendiscovered which also have hypolipidemic activity.

Accordingly, the present invention provides compounds of the formula (I)##STR2## wherein R¹ and R² are the same or different and each isoptionally substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or R¹ and R²together with the carbon atom to which they are attached form anoptionally substituted C₃₋₆ spiro-cycloalkyl group;

R⁴ is a C₆₋₁₄ aryl, or a C₃₋₁₃ heteroaryl group each optionallysubstituted with one to eight substituents which are the same ordifferent and are each selected from halogen, hydroxy, nitro,phenyl-C₁₋₆ alkoxy, C₁₋₆ alkoxy, optionally substituted C₁₋₆ alkyl,S(O)_(n) R⁸, SO₂ NR⁸ R⁹, CO₂ R⁸, O(CH₂ CH₂ O)_(n) R⁸, OSO₇ R⁸,O(CH₂)_(p) SO₃ R⁸, O(CH₂)_(p) NR⁹ R¹⁰ and O(CH₂)_(p) N⁺ R⁹ R¹⁰ R¹¹wherein R⁸ to R¹¹ are the same or different and are independentlyselected from hydrogen or optionally substituted C₁₋₆ alkyl, and whereinp is an integer from 1-4 and n is an integer from 0-3;

R^(5a), R^(5b), R^(5c), and R^(5d) each represent atoms or groups whichare the same or different and each is hydrogen. halogen, cyano, R⁸-acetylide, OR⁸, optionally substituted C₁₋₆ alkyl. COR⁸, CH(OH)R⁸,S(O)_(n) R⁸, SO₂ NR⁸ R⁹, P(O)(OR⁸)₂, OCOR⁸, OCF₃, OCN, SCN, NHCN, CH₂OR⁸, CHO, (CH₂)_(p) CN, CONR⁹ R¹⁰, (CH₂)_(p) COR⁸, (CH₂)_(p) NR⁹ R¹⁰,CO₂ R⁸, NHCOCF₃, NHSO₂ R⁸, OCH₂ OR⁸, OCH═CHR⁸, O(CH₂ CH₂ O)_(n) R⁸, OSO₂R⁸, O(CH₂)_(p) SO₃ R⁸, O(CH₂)_(p) NR⁹ R¹⁰ and O(CH₂)_(p) N⁺ R⁹ R¹⁰ R¹¹wherein R⁸ to R¹¹, n, and p are as hereinbefore defined; or R^(5a) andR^(5b), R^(5b) and R^(5c), or R^(5c) and R^(5d) together with the ringto which they are attached form a cyclic group --O(CR⁹ R¹⁰)_(m) O--wherein R⁹ and R¹⁰ are as hereinbefore defined and m is 1 or 2;

R⁶ and R⁷ are the same or different and each is hydrogen, optionallysubstituted C ₁₋₆ alkyl, C₃₋₆ cycloalkyl, or R⁶ and R⁷ together with thecarbon atom to which they are attached form an optionally substitutedC₃₋₆ spiro-cycloalkyl group;

X is CH₂, C═O, C═S, or C═NR⁸ wherein R⁸ is as hereinbefore defined; and1 is an integer from 0-2; and salts, solvates or a physiologicallyfunctional derivatives thereof.

Suitably R¹ is a C₁₋₆ alkyl group. Preferably R¹ is methyl, ethyl orn-propyl and most preferably R¹ is ethyl.

Suitably R² is a C₁₋₆ alkyl group. Preferably R² is methyl, ethyl,n-propyl, n-butyl or n-pentyl and most preferably R² is ethyl orn-butyl.

Suitably R⁴ is a phenyl group optionally substituted with one to five,preferably one or two, substituents which are the same or different andare each selected from halogen, hydroxy, nitro, phenyl-C₁₋₆ alkoxy, C₁₋₆alkoxy, optionally substituted C₁₋₆ alkyl, S(O)_(n) R⁸, CO₂ R⁸, O(CH₂CH₂ O)_(n) R⁸, OSO₂ R⁸, O(CH₂)_(p) SO₃ R⁸, O(CH₂)_(p) NR⁹ R¹⁰ andO(CH₂)_(p) N⁺ R⁹ R¹⁰ R¹¹, preferably halogen, hydroxy, nitro,phenyl-C₁₋₆ alkoxy, C₁₋₆ alkoxy, or optionally substituted C₁₋₆ alkyl.Preferably R⁴ is phenyl optionally substituted at the 3- and/or4-position by halogen, hydroxy, methyl, ethyl. methoxy, ethoxy,trifluoromethyl, hydroxy, carboxy or O(CH₂)₃ SO₃ H. Most preferably R⁴is unsubstituted phenyl or phenyl substituted at the 3- and/or4-positions with halogen, hydroxy or C₁₋₆ alkoxy, for example, methoxyor ethoxy.

Suitably R^(5a), R^(5b), R^(5c), and R^(5d) are the same or differentand are each hydrogen, C₁₋₄ alkoxy, halogen, hydroxy or C₁₋₄ alkyloptionally substituted by fluoro. Preferably R^(5a), R^(5b), R^(5c), andR^(5d) are the same or different and are each hydrogen, methyl, methoxy,hydroxy, trifluoromethyl or halo. More preferably R^(5a) and R^(5d) arehydrogen and R^(5b) and R^(5c) are the same or different and are eachhydrogen, C₁₋₄ alkoxy, halogen hydroxy, or C₁₋₄ alkyl optionallysubstituted by fluoro. Most preferably R^(5a) and R^(5d) are hydrogenand R^(5b) and R^(5c) are the same or different and are each hydrogen,methyl, methoxy, hydroxy, trifluoromethyl or halo.

Suitably R⁶ and R⁷ are the same or different and are each hydrogen or aC₁₋₆ alkyl group, for example, methyl or ethyl. Most preferably, R⁶ andR⁷ are both hydrogen.

Suitably X is CH₂ or C═O.

Suitably R⁹ to R¹¹ are the same or different and are each hydrogen ormethyl.

Suitably 1 is 0 or 2, and is preferably 2.

When one or more of R¹, R², R⁴ to R¹¹ is a substituted C₁₋₆ alkyl group,or comprises a C₁₋₆ alkyl group the substituents may be the same ordifferent and each is selected from hydroxy, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, COR¹², nitrile, CO₂ R¹², SO₃ R¹², NR¹³ R¹⁴, N⁺ R¹³ R¹⁴ R¹⁵wherein R¹² to R¹⁵ are the same or different and each is selected fromhydrogen or C₁₋₆ alkyl preferably methyl.

Further preferred compounds of formula (I) are:

(±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

(±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(±)-3-n-Butyl-2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one 1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide;

3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;

3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;

(±)-7-bromo-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

7-bromo-3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7,8-diol-1,1-dioxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7,8-diol-1,1-dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1-monoxide;

3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1-monoxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1-monoxide;

3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1-monoxide;

(±)-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;

(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one;

(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide;

(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide;

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide;

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide;

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol1,1-dioxide;

(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide; and

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7-ol1,1-dioxide.

Particularly preferred compounds include:

(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide; and

(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent, i.e., basic, compounds. Such salts must clearly have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the present inventioninclude those derived from inorganic acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulphuricacids, and organic acids, such as acetic, benzenesulphonic, benzoic,citric, ethanesulphonic, fumaric, gluconic, glycolic, isothionic,lactic, lactobionic, maleic, malic, methanesulphonic, succinic,p-toluenesulphonic, tartaric and trifluoroacetic acids. The chloridesalt is particularly preferred for medical purposes. Suitablepharmaceutically acceptable base salts include ammonium salts, alkalimetal salts, such as sodium and potassium salts, and alkaline earthsalts, such as magnesium and calcium salts.

Salts having a non-pharmaceutically acceptable anion are within thescope of the invention as useful intermediates for the preparation orpurification of pharmaceutically acceptable salts and/or for use innon-therapeutic, for example, in vitro, applications.

Any references to "compound(s) of formula (I)", "compounds of thepresent invention", "compounds according to the invention" etc., referto compound(s) of formula (I) as described above together with theirsalts, solvates and physiologically functional derivatives as definedherein.

The term "physiologically functional derivative" as used herein refersto any physiologically acceptable derivative of a compound of thepresent invention, for example, an ester, which upon administration to amammal, such as a human, is capable of providing (directly orindirectly) such a compound or an active metabolite thereof

A further aspect of the present invention is prodrugs of the compoundsof the invention. Such prodrugs can be metabolised in vivo to give acompound according to the invention. These prodrugs may or may not beactive in their own right.

The compounds of the present invention can also exist in differentpolymorphic forms, for example, amorphous and crystalline polymorphicforms. All polymorphic forms of the compounds of the present inventionare within the scope of the invention and are a further aspect thereof.

The term "alkyl" as used herein refers, unless otherwise stated, to amonovalent straight or branched chain radical. Likewise, the terms"cycloalkyl" and "spiro-cycloalkyl" refer, unless otherwise stated, to adivalent cyclic or spiro-cyclic radical respectively. The term "alkoxy"refers to a monovalent straight or branched chain radical attached tothe parent molecular moiety through an oxygen atom. The term "aryl"refers to a monovalent mono-, bi- or tri-cyclic aromatic ring. The term"heteroaryl" refers to a monovalent mono-, bi- or tri-cyclic aromaticring comprising one or more heteroatoms(e.g., nitrogen, oxygen, sulfur).The term "phenylalkoxy" refers to a monovalent phenyl group attached toa divalent C₁₋₆ alkylene group which is itself attached to the parentmolecular moiety through an oxygen atom. The term "halo" refers tofluoro, chloro, bromo, or iodo.

The compounds of formula (I) exist in forms wherein the carbon centres--C(R¹)(R²)-- and --C(R⁶)(R⁷)-- can be chiral. The present inventionincludes within its scope each possible optical isomer substantiallyfree, i.e. as associated with less than 5%, of any other opticalisomer(s), and mixtures of one or more optical isomers in anyproportions, including racemic mixtures.

In those cases where the absolute stereochemistry at --C(R¹)(R²)-- and--C(R⁶)(R⁷)-- has not been determined, the compounds of the inventionare defined in terms of the relative positions of the R¹ /R² and R⁶ R⁷substituents. Thus, those compounds wherein the bulkier of thesubstituents, i.e the substituent of higher mass are both located on thesame side of the thiazepine ring are referred to herein as "cis", andthose compounds in which the bulkier of the substituents are located onopposite sides of the ring are referred to as "trans." It will beevident to a skilled person that both "cis" and "trans" compounds of theinvention can each exist in two enantiomeric forms which areindividually designated "(+)-" or "(-)-" according to the direction ofrotation of a plane of polarised light when passed through a sample ofthe compound. Cis or trans compounds of the invention in which theindividual enantiomers have not been resolved are referred to hereinusing the prefix "(+-)-".

According to further aspects of the invention, there are also provided:

(a) the compounds of formula (I) and pharmaceutically acceptable salts,solvates and physiologically functional derivatives thereof for use astherapeutic agents, particularly in the prophylaxis and treatment ofclinical conditions for which a bile acid uptake inhibitor is indicated,for example, a hyperlipidemic condition, and associated diseases such asatherosclerosis;

(b) pharmaceutical compositions comprising a compound of formula (I) orone of its pharmaceutically acceptable salts, solvates, orphysiologically functional derivatives, at least one pharmaceuticallyacceptable carrier and, optionally, one or more other physiologicallyactive agents;

(c) the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof in the manufacture of a medicament for the prophylaxis ortreatment of a clinical condition for which a bile acid uptake inhibitoris indicated, for example, a hyperlipidemic condition, and associateddiseases such as atherosclerosis;

(d) a method of inhibiting the absorption of bile acids from theintestine of a mammal, such as a human, which comprises administering aneffective bile acid absorption inhibiting amount of a compound offormula (I) or of a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof to the mammal;

(e) a method of reducing the blood plasma or serum concentrations of LDLcholesterol in a mammal, such as a human, which comprises administeringan effective cholesterol reducing amount of a compound of formula (I) orof a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(f) a method of reducing the concentrations of cholesterol andcholesterol ester in the blood plasma or serum of a mammal, such as ahuman, which comprises administering an effective cholesterol andcholesterol ester reducing amount of a compound of formula (I) or of apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to the mammal;

(g) a method of increasing the fecal excretion of bile acids in amammal, such as a human, which comprises administering an effective bileacid fecal excretion increasing amount of a compound of formula (I) orof a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(h) a method for the prophylaxis or treatment of a clinical condition ina mammal, such as a human, for which a bile acid uptake inhibitor isindicated, for example, a hyperlipidemic condition, and associateddiseases such as atherosclerosis, which comprises administering atherapeutically effective amount of a compound of the formula (I) or ofa pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(i) a method of reducing the incidence of coronary heart disease-relatedevents in a mammal, such as a human, which comprises administering aneffective coronary heart disease-related events reducing amount of acompound of formula (I) or of a pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof;

(j) a method of reducing the concentration of cholesterol in the bloodplasma or serum of a mammal, such as a human, which comprisesadministering an effective cholesterol reducing amount of a compound offormula (I);

(k) processes for the preparation of compounds of formula (I) (includingsalts, solvates and physiologically functional derivatives thereof asdefined herein);

(l) novel chemical intermediates in the preparation of compounds offormula (I); and

(m) the compounds of synthetic Examples 1-27 as hereinafter disclosed.

The amount of a compound of formula (I) which is required to achieve thedesired biological effect will, of course, depend on a number offactors, for example, the specific compound chosen, the use for which itis intended, the mode of administration and the clinical condition ofthe recipient. In general, a daily dose is in the range of from 0.001 mgto 100 mg (typically from 0.01 mg to 50 mg) per day per kilogrambodyweight, for example, 0.01-10 mg/kg/day. Thus, orally administrableunit dose formulations, such as tablets or capsules, may contain, forexample, from 0.1 to 100 mg, typically from 0.1 to 10 mg, preferably 0.1to 5 mg. In the case of pharmaceutically acceptable salts, the weightsindicated above refer to the weight of the benzothiazepine ion derivedfrom the salt.

For the prophylaxis or treatment of the conditions referred to above,the compounds of formula (I) can be used as the compound per se, but arepreferably presented with an acceptable carrier in the form of apharmaceutical composition. The carrier must, of course, be acceptablein the sense of being compatible with the other ingredients of thecomposition and must not be deleterious to the recipient. The carriercan be a solid or a liquid, or both, and is preferably formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compound. Otherpharmacologically active substances can also be present including othercompounds of formula (I). The pharmaceutical compositions of theinvention can be prepared by any of the well known techniques ofpharmacy consisting essentially of admixing the components.

Pharmaceutical compositions according to the present invention includethose suitable for oral, rectal, topical, buccal (e.g. sub-lingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal, orintravenous) administration, although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated and on the nature of the particular compound of formula (I)which is being used. Enteric-coated and enteric-coated controlledrelease formulations are also within the scope of the invention.Suitable enteric coatings include cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate andanionic polymers of methacrylic acid and methacrylic acid methyl ester.Suitable enteric coated and enteric coated controlled releaseformulations include tablets and capsules.

Pharmaceutical compositions suitable for oral administration can bepresented in discrete units, such as capsules, cachets, lozenges, ortablets, each containing a predetermined amount of a compound of formula(I); as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such compositions can be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation the active compound and the carrier (which can constituteone or more accessory ingredients). In general, the compositions areprepared by uniformly and intimately admixing the active compound with aliquid or finely divided solid carrier, or both, and then, if necessary,shaping the product. For example, a tablet can be prepared bycompressing or moulding a powder or granules of the compound, optionallywith one or more accessory ingredients. Compressed tablets can beprepared by compressing, in a suitable machine, the compound in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent and/or surface active/dispersingagent(s). Moulded tablets can be made by moulding, in a suitablemachine, the powdered compound moistened with an inert liquid diluent.Controlled release tablets can be prepared in similar manner and withthe addition of, for example, hydroxypropylmethyl cellulose.

Enteric-coated tablets can be prepared by coating the tablets with anenteric polymer such as cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropylmethyl-cellulose phthalate, or anionic polymersof methacrylic acid and methacrylic acid methyl ester (Eudragit L™).Except for Eudragit L, these polymers should also include 10% (by weightof the quantity of polymer used) of a plasticizer to prevent membranecracking during application or on storage. Suitable plasticizers includediethyl phthalate, tributyl citrate and triacetin.

Enteric-coated controlled release tablets can be prepared by coatingcontrolled release tablets with an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

Capsules can be prepared by admixing a compound of formula (I) with, forexample, magnesium stearate, pregelantinised starch, sodium starchglycollate, and/or magnesium stearate and filling two-part hard gelatincapsules with the resulting mixture.

Controlled release capsule compositions can be prepared by admixing acompound of formula (I) with, for example, microcrystalline celluloseand/or lactose, extruding using an extruder, then spheronising anddrying the extrudate. The dried pellets are coated with a releasecontrolling membrane, for example ethyl cellulose, and filled intotwo-part, hard gelatin capsules.

Enteric capsule compositions can be prepared by admixing a compound offormula (I) with, for example, microcrystalline cellulose and/orlactose, extruding using an extruder, then spheronising and drying theextrudate. The dried pellets are coated with an enteric membrane, forexample cellulose acetate phthalate containing a plasticizer, forexample diethyl phthalate and filled into two-part, hard gelatincapsules.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of formula (I) ina flavored base, usually sucrose and acacia or tragacanth, and pastillescomprising the compound in an inert base such as gelatin and glycerin orsucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationconveniently comprise sterile aqueous preparations of a compound offormula (I), preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Such preparations canconveniently be prepared by admixing the compound with water andrendering the resulting solution sterile and isotonic with the blood.Injectable compositions according to the invention will generallycontain from 0.1 to 5% w/w of the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably presented as unit-dose suppositories. These can be preparedby admixing a compound of formula (I) with one or more conventionalsolid carriers, for example, cocoa butter, and then shaping theresulting mixture.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. Such patches suitably containthe active compound in an optionally buffered, aqueous solution,dissolved and/or dispersed in an adhesive, or dispersed in a polymer. Asuitable concentration of the active compound is about 1% to 35%,preferably about 3% to 15%. As one particular possibility, the activecompound can be delivered from the patch by electrotransport oriontophoresis, for example, as described in Pharmaceutical Research,3(6), 318 (1986).

The compounds of formulas (I) can be prepared by conventional methodsknown to a skilled person or in an analogous manner to processesdescribed in the art.

For example, compounds of formula (I) wherein i is 0, R⁶ and R⁷ arehydrogen and X is CH₂ can be prepared by reducing the carbonyl group ofa compound formula (II) ##STR3## wherein R¹,R²,R⁴ and R^(5a),b,c,d areas hereinbefore defined using, for example, a reducing agent such asaluminum hydride (AlH₃), di-isobutylaluminum hydride (DEBAL) or borane(BH₃) in a suitable organic solvent, such as THF.

Compounds of formula II as hereinbefore defined are novel and constitutea further aspect of the present invention.

Compounds of formula (II) can be prepared by a reaction of compounds offormula III ##STR4## wherein R¹,R² and R^(5a),b,c,d are as hereinbeforedefined, with the appropriate R⁴ -Z in the presence of a base, forexample potassium carbonate (K₂ CO₃) and optionally in the presence of acatalyst, for example, copper iodide(CiI) wherein R⁴ is as hereinbeforedefined and Z is a suitable leaving group, for example halo. Thecompounds R⁴ -Z are commercially available or can be prepared by methodswell known or readily available to those skilled in the art.

Compounds of formula III as hereinbefore defined are novel andconstitute a further aspect of the present invention.

Compounds of formula (III) can be prepared by cyclising compounds offormula (IV) ##STR5## wherein R¹, R² and R^(5a),b,c,d are ashereinbefore defined, by reaction with an acid, for example an organicacid such as tosic acid, preferably at an elevated temperature, forexample 255° C.

Compounds of formula (IV) can be prepared by reacting compounds offormula (V) with compounds of formula (Va) ##STR6## wherein R¹, R² andR^(5a),b,c,d are as hereinbefore defined and Z is a suitable leavinggroup, for example halo, in the presence of an organic base, for exampletriethylamine or pyrrolidine. Compounds of formulas(V) and (Va) arecommercially available or can be prepared by methods well known orreadily available those skilled in the art.

Compounds of formula (I) wherein 1 is 1 or 2, can be prepared from thecorresponding compound of formula (I) wherein 1 is 0 by oxidation of thethio moiety with a suitable oxidizing agent, for example, hydrogenperoxide, organic peroxy acids, Oxone® (potassium peroxymonosulfate), orosmium tetroxide (OSO₄).

Compounds of formula (I) wherein R⁶ and/or R⁷ are other than hydrogencan be prepared by treating the corresponding compound of formula (I)wherein 1 is 1 or 2 and R⁶ and R⁷ are hydrogen with a base, for example,n-butyllithium followed by reaction with the appropriate R⁶ -Z or R⁷ -Zwherein R⁶ and R⁷ are as defined herein other than hydrogen and Z is asuitable leaving group as defined herein.

Alternatively, compounds of formula (III) can be prepared from compoundsof formula (VI) ##STR7## wherein R¹, R² and R^(5a),b,c,d are ashereinbefore defined, by reaction with an acid, for examplepolyphosphoric acid at an elevated temperature, for example 120° C.

Compounds of formula (VI) can be prepared from compounds of formula(VII) ##STR8## wherein R¹, R² and R^(5a),b,c,d are hereinbefore defined,by reaction with hydroxyl amine (H₂ NOH).

Compounds of formula (VII) can be prepared by cyclizing compounds offormula (VIII) ##STR9## wherein R¹, R² and R^(5a),b,c,d are hereinbeforedefined, in the presence of an acid, for example sulfuric acid (H₂ SO₄).

Compounds of formula (VIII) can be prepared by reacting compounds offormula (IX) ##STR10## wherein R^(5a),b,c,d are as hereinbefore defined,with compounds of formula (VI) analogous to the preparation of compoundsof formula (IV) described hereinbefore.

Compounds of formula (IX) are commercially available or can be preparedby methods well known or readily available to those skilled in the art.

Alternatively, compounds of formula (H) can be prepared by cyclizingcompounds of formula (X) ##STR11## wherein R¹, R², R⁴, and R^(5a),b,c,dare as hereinbefore defined, in the presence of an organic acid, forexample tosic acid.

Compounds of formula (X) can be prepared from compounds of formula (XI)##STR12## wherein R⁴ and R^(5a),b,c,d are as herein before defined, withcompounds of formula (Va) analogous to the preparation of compounds offormula (IV) described hereinbefore.

Compounds of formula (I) can be prepared by methods well known orreadily available to those skilled in the art, for example by themethods disclosed in H. Gilman and J. Dietrich, J. Am. Chem. Soc., 80,380-383 (1958).

Compounds of formula (I) wherein X is C═O can be prepared following themethod for the preparation of compounds of formula (II) describedhereinbefore.

Compounds of formula (I) wherein X is C═S can be prepared from thecorresponding compounds of formula (I) wherein X is C═O by conversion ofthe C═O moiety with, for example, Lawesson'sReagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide).

The compounds of formula (I) substantially free, of other opticalisomers can be obtained either by chiral synthesis, for example, by theuse of the appropriate chiral starting material(s), such as a chiralcompound of formula (Va), or by resolution of the products obtained fromachiral syntheses, for example, by chiral hplc, enzymatic resolution, orby classical resolution with chiral acids.

Optional conversion of a compound of formula (I), or a compound offormula (I) comprising a basic substituent, to a corresponding acidaddition salt may be effected by reaction with a solution of theappropriate acid, for example, one of those recited earlier. Optionalconversion of a compound of formula (I) comprising an acidic substituentto a corresponding base salt may be effected by reaction with a solutionof the appropriate base, for example, sodium hydroxide. Optionalconversion to a physiologically functional derivative, such as an ester,can be carried out by methods known to those skilled in the art orobtainable from the chemical literature.

In addition, compounds of the formula (I) may be converted to differentcompounds of the formula (I) by standard methods known or available fromthe literature to those skilled in the art, for example by alkylation ofa hydroxy group.

For a better understanding of the invention, the following Examples aregiven by way of illustration and are not to be construed in any way aslimiting the scope of the invention.

General Procedures. Proton magnetic resonance spectra were recorded at300 MHz. Mass spectra were recorded under atmospheric pressure chemicalionization (APCI) conditions on a LCMS instrument or were performed byOneida Research Services, Inc. under chemical ionization (CI) conditionsusing methane as the reagent gas. Elemental Analysis were performed byAtlantic Microlab, Inc. All reactions were performed under nitrogenatmosphere. TLC plates were Whatman MK6F silica gel 60 plates and werevisualized under a UV lamp. Column chromatography was performed with EMScience silica Gel 60 (230-400 mesh). Reagents were obtained fromAldrich Chemical Co. unless otherwise noted and were used withoutfurther purification. Solvents were Aldrich anhydrous grade.

EXAMPLE 1

Preparation of(±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

(a) (1)-2-((Tert-butyldimethylsilyl)oxy)methyl-ethyl-hexanol.

To a slurry of 60% NaH (7.5 g, 187.2 mmol) in 400 ml THF was added in 3portions 2-n-butyl-2-ethyl-1,3-propanediol (30.0 g, 187.2 mmol) andstirred for 45 min. To the resulting gum was addedtert-butyldimethylsilyl chloride (28.2 g, 187.2 mmol) and stirred for 2h. The solvent was evaporated and the residue was partitioned betweenwater and ether. The ether layer was washed with bicarbonate solutionand brine and concentrated. Column chromatography (5% ethylacetate/petroleum ether) gave the title compound as a colorless oil(50.12 g, 182.6 mmol, 98%). ¹ H NMR (DMSO-d₆) δ 4.19 (t, 1H); 3.29 (s,2H); 3.13 (d, 2H); 1.15 (m, 8H); 0.84 (s, 9H); 0.83 (t, 3H); 0.73 (t,3H); -0.01 (s, 6H). MS Da/e=275 (MH⁺). Calcd for C₁₅ H₃₄ O₂ Si: C,65.63; H, 12.48. Found: C, 65.87; H, 12.47.

(b) (±)-2-Ethyl-2-(hydroxymethyl)-hexanoic acid.

To a solution of the product of Example 1(a) (4.43 g, 16.0 mmol) in 16ml CCl₄, 16 ml CH₃ CN, and 24 ml H₂ O was added NaIO₄ (13.69 g, 64 mmol)and RuCl₃ (0.16 g, 0.8 mmol) and stirred for 16 h. The slurry wasconcentrated and the solvents evaporated. The residue was partitionedbetween H₂ O and CH₂ Cl₂. The aqueous phase was extracted 3 times withCH₂ Cl₂, dried, concentrated. The residue was dissolved in 3 ml THF, 1Mtetrabutylammonium fluoride in THF (1.75 ml, 1.75 mmol) was added andthe solution was stirred for 1 h. The solvent was evaporated, and theresulting oil was partitioned between H₂ O and CH₂ Cl₂. The aqueousphase was extracted 3× with CH₂ Cl₂, dried, concentrated. Columnchromatography (95% CH₂ Cl₂ /4% MeOH/0.5% H₂ O/0.5% acetic acid) gavethe product as an oil 2.26 g (13.0 mmol, 81%). ¹ H NM (DMSO-d₆) δ 11.95(br s, 1H); 4.74 (br s, 1H); 3.42 (s, 2H); 1.53-1.03 (m, 8H); 0.84 (t,3H); 0.73 (t, 3H). MS Da/e=175 (MH⁺) and 129 (M-CO₂ H). Calcd for C₉ H₁₈O₃ : C, 62.04: H, 10.41. Found: C, 61.94; H, 10.44.

(c) (±)-2-(Bromomethyl)-2-ethyl-hexanoic acid.

A solution of the product from Example 1(b) (2.30 g, 13.2 mmol) in 48%HBr (40 ml) was refluxed for 20 h. After cooling to RT the solution wastransferred to a separatory funnel, extracted 3 times with ethylacetate, dried over Na₂ SO₄, and concentrated. After pumping at highvacuum to remove traces of HBr, obtained the title compound (2.46 g,10.4 mmol. 79%). ¹ H NMR (DMSO-d₆) δ 3.60 (s, 2H); 1.62-1.04 (m, 8H);0.85 (t, 3H); 0.75 (t, 3H). MS Da/e=157 (M-Br), 237 (M), 238, 239 (M-2).Calcd for C₉ H₁₇ O₂ Br: C, 45.59; H, 7.23; Br, 33.70. Found: C, 46.27;H, 7.17; Br, 32.94.

(d) (±)-2-(((2-Aminophenyl)thio)methyl)-2-ethylhexanoic acid.

To a solution of the product from Example 1(c) (0.52 g, 2.19 mmol) inTHF (4 ml) was added 2-aminothiophenol (0.41 g, 3.29 mmol, freshlydistilled) and pyrollidine (or triethylamine, 3.29 mmol) and stirred for48 h. The reaction mixture was transferred to a separatory funnel andpartitioned between H₂ O and CHCl₃. The aqueous layer was extracted 3times with CHCl₃, column chromatographed (30% ethyl acetate in petroleumether) to give the title compound (0.50 g, 1.78 mmol, 81%). ¹ H NMR(DMSO-d₆) δ 12.40 (br s, 1H); 7.25 (d, 1H); 7.00 (t, 1H); 6.67 (d, 1H);6.48 (t, 1H); 5.23 (br, s, 2H); 2.91 (s, 2H); 1.66-0.99 (m, 8H); 0.77(t, 3H); 0.67 (t, 3H). MS Da/e=282 (MH⁺), 264 (M-H₂ O), 236 (M-CO₂ H).Calcd for C₁₅ H₂₃ NSO₂ ×(0.8 EtOAc): C, 62.12; H, 8.42; N, 3.98; S,9.11. Found: C, 62.41; H, 8.28; N, 3.83; S, 8.91.

(e) (±)-3-n-Butyl-3-ethyl-2,3-dihydro-1,5-benzothiazepin-4-one.

A solution of the product from Example 1(d) (0.66 g, 2.35 mmol) andtoluenesulfonic acid (0.15 g, 0.79 mmol) in tetradecane (30 ml) wasrefluxed for 3 h. After cooling to RT the reaction miture was loadeddirectly onto a silica column and the product eluted with 10% ethylacetate/petroleum ether yielding the title compound (0.44 g, 167 mmol,71%). M.P.=90.0° C. ¹ H NMR (DMSO-d₆) δ 9.71 (s, 1H); 7.39 (d, 1H); 7.23(t, 1H); 7.10 (d, 1H); 6.95 (t, 1H); 2.92 (s, 2H); 1.72-1.20 (m, 4H);1.15 (m, 4H); 0.78 (m, 6H). MS Da/e=264 (MH⁺). Calcd for C₁₅ H₂₁ NSO: C,68.40; H, 8.04; N, 5.32. S, 12.17. Found: C, 68.25; H, 8.11; N, 5.29; S,12.09.

(f) (±)-3-n-Butyl-3-ethyl-2 3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

To a solution of the product from Example 1(e) (4.07 g, 15.45 mmol) inphenyl iodide (17 ml, 154 mmol) was added copper iodide (0.28 g, 1.5mmol) and potassium carbonate (2.13 15.45 mmol), and the mixture wasrefluxed for 16 h. The reaction mixture was allowed to cool and wasloaded directly onto a silica column and eluted with 5% ethylacetate/petroleum ether to give the title compound (5.14 g, 15.14 mmol,98% yield). M.P.=159.4° C. ¹ H NMR (DMSO-d₆) δ 7.67-6.86 (m, 9H); 3.11(s, 2H); 1.58-1.13 (m, 8H); 0.77 (m, 6H). MS Da/e=340 (MH⁺). Calcd forC₂₁ H₂₅ NSO: C, 74.30; H, 7.42; N, 4.13; S, 9.44. Found: C, 74.11, H,7.49; N, 4.03; S, 9.36.

EXAMPLE 2

Preparation of(±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide.

To a solution of the compound of Example 1(f) (0.95 g, 2.80 mmol) intrifluoroacetic acid (9.5 ml) at 0° C. was added 30% hydrogen peroxide(1.60 g, 14 mmol) and stirred for 16 h. The solution was neutralizedwith sodium carbonate solution and the product extracted 3 times withethyl acetate. The organic extracts were dried (Na₂ SO₄), concentratedand the resulting oil loaded onto a silica column. The product waseluted with 20% ethyl acetate/petroleum ether giving the title compoundas a white powder (0.96 g, 2.58 mmol, 92%). M.P.=57.6° C. ¹ H NMR(DMSO-d₆) δ 7.94-7.06 (m, 9H); 3.73 (s, 2H), 1.72-0.98 (m, 8H); 0.77 (m,6H). MS Da/e=372 (MH⁺). Calcd for C₂₁ H₂₅ NSO₃ : C, 67.90, H, 6.78; N,3.77; S, 8.63. Found: C, 67.61; H, 6.92; N, 3.62; S, 8.57.

EXAMPLE 3

Preparation of(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine.

To a solution of AlH₃ (44 mmol, generated in situ from H₂ SO₄, 22 mmol,and LiAlH₄, 44 mmol) in 44 ml diethyl ether was added the compound ofExample 1(f) (5.00 g, 14.60 mmol) in 40 ml THF at 0° C. The reactionmixture was allowed to warm to RT over 2 h and was stirred at RT for 15h after which time TLC (20% ethyl acetate/petroleum ether) showedcomplete reaction. The reaction flask was cooled to 0° C. and the excessAlH₃ was quenched by adding 30 of H₂ O/THF (1:2) dropwise followed by 5ml 1M NaOH. The mixture was transferred to a separatory funnel andextracted 3 times with ether. The ether extracts were combined, dried,concentrated and column chromatographed (petroleum ether) to give thetitle compound (4.74 g, 14.55 mmol, 99%). ¹ H NMR (DMSO-d₆) δ 7.26-6.69(m, 9H); 3.67 (br s, 2H); 2.78 (m, 2H); 1.21-1.05 (m, 8H); 0.71 (m, 6H).MS Da/e=325 (M⁺), 326 (MH⁺). Calcd for C₂₁ H₂₇ NS: C, 77.49; H, 8.36; N,4.30; S, 9.85. Found: C, 77.51; H, 8.40; N, 4.31, S, 9.73.

EXAMPLE 4

Preparation of(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide.

To a solution of the compound of Example 3 (4.73 g, 14.53 mmol) in 100ml THF and 23 ml tert-butanol was added N-methyl-morpholine-N-oxide (5.1g, 43.6 mmol) and osmium tetroxide (0.8 mmol, 2.5 wt % in2-methyl-2-propanol). The mixture was stirred at RT for 16 h at whichpoint 50 ml NAHCO₃ solution was added to neutralize any acid, themixture transferred to a separatory funnel and extracted 3 times withethyl acetate. The organic layers were washed with sodium hyposulfiteand brine, dried (Na₂ SO₄) and concentrated. Column chromatography (10%ethyl acetate/petroleum ether) yielded the title compound (4.76 g, 13.3mmol, 92% yield). ¹ H NMR (DMSO-d₆) δ 7.87-6.81 (m, 9H); 3.72 (m, 2H);3.33 (s, 2H); 1.55-0.97 (m, 8H); 0.69 (m, 6H). MS Da/e=358 (MH⁺). Calcdfor C₂₁ H₂₇ NSO₂ : C, 70.55; H, 7.61; N, 3.92; S, 8.97. Found: C, 70.37;H, 7.59; N, 3.84; S, 9.07.

EXAMPLE 5

Preparation of(±)-3-n-Butyl-2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide.

To a solution of the compound of Example 4 (0.565 g, 1.58 mmol) in 10 mlTHF was added n-butyllithium (2.5 M in THF, 1.74 mmol) at -78° C. Thiswas stirred for 20 min at -78° C. after which iodo-2-methylpropane (1.3M in THF, 6.32 mmol) was added dropwise at -78° C. The reaction mixturewas brought up to 0° C. and stirred for 16 h. The excess base wasquenched by adding brine (10 ml) and the product was extracted withether (3×20 ml). The ether extracts were dried, concentrated and theresidue applied to a silica gel column. The product was eluted with 10%ethyl acetate/petroleum ether giving a yellow oil, (0.48 g, 1.16 mmol,74%). ¹ H NMR (DMSO-d₆) δ 7.89-6.80 (m, 9H); 3.30 (br m, 2H); 3.09 (brs, 1H); 1.88-0.63 (m, 23H). MS Da/e=414 (MH⁺), 436 (M+Na). Calcd for C₂₅H₃₅ NSO₂ :l C, 72.60; H, 8.53; N, 3.39; S, 7.75. Found: C, 72.39; H,8.56; N, 3.27; S, 7.88.

EXAMPLE 6

Preparation of3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

(a) 2-((Tert-butyldimethylsilyl)oxy)methyl-2-ethylbutanol.

The title compound was prepared from 2,2-diethyl-1,3-propanediolaccording to the procedure for Example 1(a) ¹ H NMR (DMSO-d₆) δ 4.20 (t,1H); 3.29 (s, 2H); 3.14 (d, 2H); 1.13 (q, 4H); 0.84 (s, 9H); 0.73 (t,6H); 0.73 (t, 3H); -0.01 (s, 6H). MS Da/e=247 (MH⁺). Calcd for C₁₃ H₃₀O₂ Si: C, 63.35; H, 12.26. Found: C, 63.27; H, 12.25.

(b) 2-Ethyl-2-(hydroxymethyl)-butyric acid.

The title compound was prepared from the product of Example 6(a)(41.28g, 189 mmol) using the procedure for Example 1(b) yielding (24.4 g, 167mmol, 88%). ¹ H NMR (DMSO-d₆) δ 3.42 (s, 2H); 1.89 (s, 1H); 1.44 (q,4H); 0.73 (t, 6H). MS Da/e=147 (MH⁺). Calcd for C₇ H₁₄ O₃ ×0.3(AcOH): C,55.39; H, 9.33. Found: C, 55.381, R 9.17.

(c) 2-(Bromomethyl)-2-ethylbutyric acid.

The title compound was prepared from the product of Example 6(b) (22.2g, 151 mmol) according to the procedure outlined for Example 1(c). Afterremoving the HBr in vacuo obtained 10B (19.8 g, 94.7 mmol, 63%). ¹ H NMR(DMSO-d₆) δ 3.60 (s, 2H); 1.58 (q, 4H); 0.75 (t, 3H). MS Da/e=209 (M),211 (M+2). Calcd for C₇ H₁₃ O₂ Br: C, 40.21; H, 6.27; Br, 38.21. Found:C, 40.92; H, 6.38; Br, 37.17.

(d) 2-(((2-Aminophenyl)thio)methyl)-2-ethylbutyric acid.

The title compound was prepared from the compound of Example 6(c) (19.7g, 94 mmol) according to the procedure for Example 1(d). Columnchromatography yielded the product (9.77 g, 40 mmol, 43%). ¹ H NMR(DMSO-d₆) δ 7.24 (d, 1H); 7.00 (t, 1H); 6.69 (d, 1H); 6.49 (t, 1H); 2.91(s, 2H); 1.60 (q, 4H); 0.68 (t, 3H). MS Da/e=254 (MH⁺). Calcd for C₁₃H₁₉ NSO₂ : C, 61.62; H, 7.57; N, 5.52; S, 12.65. Found: C, 61.34; H,7.62; N, 5.33; S, 12.40.

(e) 3,3-Diethyl-2,3-dihydro-1,5-benzothiazepin-4-one

The title compound was prepared by thermal ring closure of the productof Example 6(d) (9.7 g, 38 mmol) as outlined for Example 1(e). Columnchromatography (50% ethyl acetate/petroleum ether) yielded the titlecompound (6.22 g, 26.4 mmol, 70% yield). ¹ H NMR (DMSO-d₆) δ 9.73 (s,1H); 7.40 (d, 1H); 7.23 (t, 1H); 7.10 (d, 1H); 6.97 (t, 1H); 2.92 (s,2H); 1.71-1.48 (m, 4H); 0.76 (m, 6H). MS Da/e=236 (M⁺). Calcd for C₁₃H₁₇ NSO: C, 66.34; H, 7.28; N, 5.95; S, 13.67. Found: C, 66.34; H, 7.37;N, 5.96; S, 13.58.

(f) 3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

The N-phenylation of the compound from Example 6(e) (5.40 g, 23 mmol)was accomplished following the procedure for Example 1(f) to yield thetitle compound after column chromatography (7.04 g, 22.6 mmol, 99%yield). M.P.=86.4° C. ¹ H NMR (DMSO-d₆) δ 7.66-6.87 (m, 9H); 3.09 (s,2H); 1.45 (m, 4H); 0.76 (m, 6H). MS Da/e=312 (MH⁺). Calcd for C₁₉ H₂₁NSO: C, 73.21; H, 6.79; N, 4.49; S, 10.29. Found: C, 73.36, H, 6.90; N,4.49; S, 10.42.

EXAMPLE 7

Preparation of 3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one1,1-dioxide.

The oxidation of the compound of Example 6(f) (2.00 g, 6.4 mmol) to thesulfone was accomplished by the procedure outlined for Example 2. Columnchromatography (50% ethylacetate/petroleum ether) gave the title product(1.92 g, 5.59 mmol, 88% yield). M.P.=163.0-165.6° C. ¹ H NMR (DMSO-d₆) δ7.94-7.07 (m, 9H); 3.72 (s, 2H); 1.80-1.22 (br m, 4H); 0.76 (m, 6H). MSDa/e=344 (MH⁺), 366 (M+Na⁺). Calcd for C₁₉ H₂₁ NSO₃ : C,66.44, H, 6.16N, 4.07; S, 9.33. Found: C, 66.22; H, 6.21; N, 4.06; S, 9.42.

EXAMPLE 8

Preparation of3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine

The reduction of the compound of Example 6(f) (2.43 g, 7.80 mmol) wasaccomplished by the procedure outlined for Example 3. Columnchromatography (20% ethylacetate/petroleum ether) gave the title product(2.01 g, 6.76 mmol, 87% yield). ¹ H NMR (DMSO-d₆) δ 7.29-6.71 (m, 9H);3.65 (br s, 2H); 2.77 (s, 2H); 1.36-1.15 (m, 4H); 0.67 (m, 6H). MSDa/e=298 (MH⁺). Calcd. for C₁₉ H₂₃ NS: C, 76.71; H, 7.79 N, 4.70; S,10.77. Found: C, 76.64; H, 7.82; N, 4.69; S, 10.72.

EXAMPLE 9

Preparation of3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide.

The oxidation of the compound of Example 8 (0.53 g, 1.80 mmol) wasaccomplished by the procedure outlined for Example 4. Columnchromatography (50% ethyl acetate/petroleum ether) gave the titleproduct as a yellow solid, (0.55 g, 1.67 mmol, 93% yield).M.P.=128.0-130.2° C. ¹ H NMR (DMSO-d₆) δ 7.88-6.84 (m, 9H); 3.73 (br s,2H); 3.32 (s, 2H); 1.55-1.30 (m, 4H); 0.68 (m, 6H). MS Da/e=330 (MH⁺),352 (M+Na⁺). Calcd. for C₁₉ H₂₃ NSO₂ : C, 69.27; H, 7.04 N, 4.25, S,9.73. Found: C, 69.06; H, 7.16; N, 4.16; S, 9.56.

EXAMPLE 10

Preparation of3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

(a) Bromopivalic acid

The title compound was prepared from hydroxypivalic acid (TCI America,50.0 g, 423 mmol) using the procedure for Example 1(c). After removingthe HBr under high vacuum the product was obtained (66.42 g, 367 mmol,87%). ¹ H NMR (DMSO-d₆) δ 12.3 (br s); 3.57 (s, 2H); 1.19 (s, 6H). MSDa/e=181 (M), 183 (M+2). Calcd for C₅ H₉ O₂ Br: C, 33.17; H, 5.01; Br,44.13. Found: C, 34.07; H, 5.08; Br, 42.45.

(b) 2-(((2-Aminophenyl)thio)methyl)-2-methylpropionic acid.

Bromopivalic acid (Example 10(a)) (59.4 g, 328 mmol) was reacted with2-aminothiophenol (41 g, 328 mmol, freshly distilled) according to theprocedure for Example 1(d). Column chromatography yielded the titlecompound (52.3 g, 232 mmol, 71%). ¹ H NMR (DMSO-d₆) δ 12.44 (br s, 1H);7.22 (d, 1H); 6.99 (t, 1H); 6.63 (d, 1H); 6.47 (t, 1H); 5.27 (br s, 2H);2.88 (s, 2H); 1.14 (s, 6H). MS Da/e=226 (MH⁺), 208 (M-H₂ O), 180(M-CO₂). Calcd for C₁₁ H₁₅ NSO₂ : C, 58.64; H, 6.71; N, 6.22; S, 14.23.Found: C, 58.41; H, 6.78; N, 6.13; S, 14.29.

(c) 3,3-Dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one

The title compound was prepared by thermal ring closure of the compoundof Example 10(b) (33.4 g, 148 mmol) as outlined for Example 1(e). Columnchromatography (25% ethyl acetate/petroleum ether) yielded the product(25.39 g, 122 mmol, 83% yield). M.P.=112.6° C. ¹ H NMR (DMSO-d₆) δ 9.71(s, 1H); 7.40 (d, 1H); 7.23 (t, 1H); 7.11 (d, 1H), 6.96 (t, 1H); 2.95(s, 2H); 1.18 (s, 6H). MS Da/e=208 (MH⁺). Calcd for C₁₁ H₁₃ NSO: C,63.74; H, 6.32; N, 6.76; S, 15.47. Found: C, 63.94; H, 6.37; N, 6.56; S,15.28.

(d) 3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

The N-phenylation of the compound of Example 10(c) (22.0 g, 106 mmol)was accomplished following the procedure for Example 1(f) to yield,after column chromatography, the title compound (28.69 g, 101 mmol, 96%yield). M.P.=103.8° C. ¹ H NMR (DMSO-d₆) δ 7.68-6.88 (m, 9H); 3.19 (s,2H); 1.05 (s, 6H). MS Da/e=284 (MH⁺), 306 (M+Na⁺). Calcd for C₁₇ H₁₇NSO: C, 72.05; H, 6.05; N, 4.94; S, 11.31. Found: C, 71.85; H, 6.13, N,4.85; S, 11.26.

EXAMPLE 11

Preparation of3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide.

The oxidation of the compound of Example 10(d) (8.69 g, 30.7 mmol) wasaccomplished following the procedure for Example 2 to give, after columnchromatography and oven drying, a white powder, the product as (8.80 g,27.9 mmol, 91% yield). M.P.=140.8° C. ¹ H NMR (DMSO-d₆) δ 7.95-7.04 (m,9H); 3.81 (s, 2H); 1.10 (s, 6H). MS Da/e=316 (MH⁺), 338 (M+Na⁺). Calcdfor C₁₇ H₁₇ NSO₃ ×(0.5 H₂ O): C, 62.94; H, 5.59; N, 4.32; S, 9.88.Found: C, 62.98; H, 5.28; N, 4.26; S, 9.68.

EXAMPLE 12

Preparation of3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine.

The reduction of the compound of Example 11 (8.88 g, 31.05 mmol) wasaccomplished following the procedure for Example 3 to give the product,after column chromatography (5% ethyl acetate/petroleum ether), as ayellow oil (8.02 g, 29.77 mmol, 96% yield). ¹ H NMR (DMSO-d₆) δ7.44-6.68 (m, 9H); 3.31 (br s, 2H); 2.65 (s, 2H); 0.93 (s, 6H). MSDa/e=270 (MH⁺). Calcd for C₁₇ H₁₉ NS: C, 75.79; H, 7.11; N, 5.20; S,11.90. Found: C, 75.82; H. 7.06; N, 5.28; S, 11.86.

EXAMPLE 13

Preparation of2,3,4,5-Tetrahydro-3,3-dimethyl-5-phenyl-1,5-benzothiazepine-1,1-dioxide.

The oxidation of the compound of Example 12 (5.66 g, 21.01 mmol) wasaccomplished following the procedure for Example 4 to give, after columnchromatography (20% ethyl acetate/petroleum ether), a white powder (5.56g, 18.45 mmol, 88% yield). M.P.=168.0-168.6° C. ¹ H NMR (DMSO-d₆) δ7.92-6.83 (m, 9H); 3.66 (br s, 2H); 3.33 (s, 2H); 1.03 (s, 6H). MSDa/e=302 (MH⁺), 324 (M+Na⁺). Calcd for C₁₇ H₁₉ NSO₂ : C, 67.75; H, 6.35;N, 4.65; S, 10.65. Found: C, 67.85; H, 6.44; N, 4.68; S, 10.71.

EXAMPLE 14

Alternative preparation of(±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

(a) 2-Anilinobenzenethiol.

This was prepared according to a procedure from H. Gilman and J.Dietrich, J. Am. Chem. Soc. 80 (1958) pp. 380-383. To a solution ofphenothiazine (10.0 g, 50.2 mmol) in 50 ml THF was added strips oflithium (2.0 g, 288 mmol) over 45 min. The mixture was stirred for 1 hafter which time the solution was pipetted off the unreacted lithium andpartitioned between ether and water in a separators funnel. The productwas extracted with 4 N NaOH. The ether layer yielded unreactedphenothiazine (4.02 g, 20 mmol, 40%). The aqueous base layer wasneutralized to pH 4 and extracted with ether 3 times. The ether layerwas dried, concentrated and the residue chromatographed (5% ethylacetate/petroleum ether) giving the title compound (5.49 g, 27.3 mmol,55% yield). ¹ H NMR (DMSO-d₆) δ 7.65-6.74 (m, 9H). MS Da/e=202 (MH⁺).Calcd for C₁₂ H₁₁ NS: C, 71.61; H, 5.51; N, 6.96; S. 15.93. Found: C,71.66; H, 5.46, N, 6.92; S, 15.90.

(b) (±)-2-(((2-Anilinophenyl)thio)methyl)-2-ethylhexanoic acid.

This was prepared by reacting the compound of Example 14(a) (3.06 g,15.2 mmol) with the compound of Example 1(c) (3.50 g, 15.0 mmol)according to the procedure used to prepare in Example 1(d). Columnchromatography (50% ethyl acetate/petroleum ether) gave the titlecompound (3.70 g, 10.4 mmol, 70%). ¹ H NMR (DMSO-d₆) δ 12.48 (br s, 1H);7.46-6.83 (m, 9H); 3.01 (s, 2H); 1.55-1.03 (m, 8H); 0.73 (m, 6H). MSDa/e=358 (MH⁺). Calcd for C₂₁ H₂₇ NSO₂ : C, 70.55; H, 7.61; N, 3.91; S,8.96. Found: C, 70.61; H, 7.62; N, 3.85; S, 8.88.

(c) (±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

The ring closure of the compound of Example 14(b) (0.59 g, 1.65 mmol)was carried out using the procedure for Example 1(e) giving the titlecompound (0.17 g, 0.51 mmol, 31% yield). ¹ H NMR (DMSO-d₆) is identicalto product of Example 1(f) described above.

EXAMPLE 15

Preparation of(±)-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one.

(a) 2-Amino-5-methoxythiophenol

A solution of 2-amino-6-methoxybenzothiazole (36 g, 200 mmol; AldrichChemical Co.) and 400 ml 30% aqueous potassium hydroxide was refluxedfor 16 h. The dark solution was cooled to 0° C. and neutralized to pH 6with 50% aqueous acetic acid and stirred for 1 h. The resulting slurrywas filtered and the product collected on the filter paper and dried(25.29 g, 81% yield). ¹ H NMR (DMSO-d₆) δ 6.91-6.44 (m, 3H), 5.90 (br s,2H). 3.52 (s, 3H). MS Da/e=154 (M-H).

(b)(±)-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-1,5-benzothiazepin-4(5H)-one.

To a solution of the compound of Example 1(c) (25.1 g, 105.8 mmol) in150 ml dimethylformamide was added the compound of Example 15(a) (13.7g, 88.2 mmol) and 13 ml triethylamine. The mixture was stirred overnightand then transferred to a separatory funnel with 200 ml water. The pHwas adjusted to 4 with 0.1 N HCl and the product was extracted with 6×50ml diethyl ether. The ether extracts were pooled, dried and the solventevaporated to give a viscous oil. To this was added 200 ml tetradecaneand 825 mg p-toluenesulfonic acid and the mixture refluxed for 1.5 h.The reaction mixture was cooled and loaded onto a silica gel column andthe product eluted with 20% ethyl acetate/petroleum ether (15.15 g, 59%yield). M.P.=100.4° C. ¹ H NMR (DMSO-d₆) δ 9.51 (s, 1H); 7.96-6.81 (m,3H); 3.70 (s, 3H); 2.94 (S, 2H); 1.71-1.39 (mn, 4H); 1.19-1.13 (m, 4H);0.79 (t, 3H); 0.74 (t, 3H). MS Da/e=294 (MH⁺). Calcd for C₁₆ H₂₃ NSO₂ :C, 65.49; H, 7.90; N, 4.77; S, 10.93. Found: C, 65.39; H. 7.94; N, 4.80;S, 10.85.

(c)(±)-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one.

The compound of Example 15(b) (11.0 g, 37.5 mmol) was reacted withphenyl iodide using the procedure outlined for Example 1(f) to give theproduct (13.07 g, 94% yield). ¹ H NMR (DMSO-d₆) δ 7.54-6.79 (m, 8H);3.75 (s, 3H); 3.11 (s, 2H); 1.51-1.13 (m, 8H); 0.77 (m, 6H). MS Da/e=370(MH⁺). Calcd for C₂₂ H₂₇ NSO₂ ×0.75 H₂ O: C, 68.99; H, 7.50; N, 3.66; S,8.35. Found: C, 68.95; H, 7.14; N, 3.63; S, 8.25.

EXAMPLE 16

Preparation of(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine.

The compound of Example 15(c) (2.25g, 6.10 mmol) was reacted with AlH₃using the procedure outlined for Example 3 to give the product (1.95 g,90% yield). ¹ H NMR (DMSO-d₆) δ 7.11-6.65 (m, 8H,); 3.70 (s, 3H); 3.51(br s, 2H); 2.66 (s, 2H); 1.40-1.10 (m, 8H); 0.72 (m, 6H). MS Da/e=356(MH⁺). Calcd for C₂₂ H₂₉ NSO: C, 74.32; H, 8.22; N, 3.94, S, 9.02.Found: C, 74.20; H. 8.16, N, 3.88; S, 8.95.

EXAMPLE 17

Preparation of(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide.

The compound of Example 16 (1.52 g, 4.28 mmol)was oxidized to thesulfone in analogy with the procedure outlined for Example 4 giving theproduct (1.61 g, 97% yield). ¹ H NMR (DMSO-d₆) δ 7.35-6.79 (m, 8H); 3.80(s, 3H); 3.65 (br s, 2H); 3.26 (s, 2H); 1.51-1.02 (m, 8H); 0.73 (m, 6H).MS Da/e=388 (MH⁺). Calcd for C₂₂ H₂₉ NSO₃ : C, 68.18; H, 7.54; N, 3.61;S. 8.27. Found: C, 68.13; H, 7.59; N, 3.57; S, 8.21.

EXAMPLE 18

Preparation of(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide.

To a mixture of aluminum bromide (1M in CH₂ Cl₂, 16 mmol) andethanethiol (7.4 ml, 100 mmol) at 0° C. was added the compound ofExample 17 (0.78 g, 2.01 mmol) in 30 ml CH₂ Cl₂. The mixture was stirredfor 1 h at 0° C. and then 25 ml water was added and the productextracted with 3×20 ml CH₂ Cl₂. The organic layer was dried and thesolvents evaporated. The residue was applied to a silica gel column andthe product eluted with 35% ethyl acetate/petroleum ether (0.74 g, 98%).¹ H NMR (DMSO-d₆) δ 10.00 (s, 1H), 7.28-6.74 (m, 8H); 3.6 (br s, 2H);3.21 (s, 2H); 1.55-1.02 (m, 8H); 0.73 (m, 6H). MS Da/e=374 (MH⁺). Calcdfor C₂₁ H₂₇ NSO₃ ×0.4 H₂ O: C, 66.25; H, 7.36; N, 3.68; S, 8.42. Found:C, 66.12; H. 7.37; N, 3.61; S, 8.30.

EXAMPLE 19

Preparation of(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one.

(a)(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-1,5-benzothiazepin-4(5H)-one.

To a solution of the compound of Example 15(c) (5.59 g, 19.05 mmol) inmethylene chloride (120 ml) at 0° C. was added N-bromosuccinimide (6.78g, 38.10 mmol) and stirred for 30 min. The reaction mixture was washedonce with water and the organic layer was dried, concentrated, and theresidue loaded onto a silica gel column. The product was eluted with 10%ethyl acetate/petroleum ether (6.60 g, 93% yield). M.P=102.0° C. ¹ H NMR(DMSO-d₆) δ 9.60 (s, 1H); 7.31 (s, 1H); 7.09 (s, 1H), 3.80 (s, 3H); 2.91(S, 2H); 1.71-1.39 (m, 4H); 1.19-1.13 (m, 4H); 0.80 (t, 3H); 0.75 (t,3H). MS Da/e=372, 374 (MH⁺). Calcd for C₁₆ H₂₂ BrNSO₂ : C, 51.62; H,5.96; N, 3.76, S, 8.61. Found: C, 51.33; H. 5.87; N, 3.65; S, 8.44.

(b)(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one.

To a solution of the compound of Example 19(a) (6.60 g, 17.7 mmol) inbromobenzene (35 ml) was added copper bromide (500 mg) and potassiumcarbonate (2.5 g), and the mixture was refluxed for 20 h. The reactionmixture was loaded onto a silica gel column and the product eluted with10% ethyl acetate/petroleum ether (5.05 g, 64% yield). M.P.=131.0-132.8°C. ¹ H NMR (DMSO-d₆) δ 7.40-7.05 (m, 7H); 3.88 (s, 3H); 3.14 (s, 2H);1.55-1.03 (m, 8H); 0.77 (m, 6H). MS Da/e=448, 450 (MH⁺). Calcd for C₂₂H₂₆ BrNSO₂ ×0.3H₂ O: C, 58.23; H. 5.91; N, 3.09; Br, 17.61. Found: C,58.25; H, 5.96; N, 3.05; Br, 17.56.

EXAMPLE 20

Preparation of(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide.

To a solution of AlH₃ (29 mmol, generated in situ from H₂ SO₄, 15.5mmol, and LiAlH₄, 29 mmol) in 29 ml diethyl ether was added the compoundof Example 19(b) (4.38 g, 9.77 mmol) in 15 ml THF at 0° C. The reactionmixture was allowed to warm to RT over 2 h and was stirred at RT for 15h after which time TLC (20% ethyl acetate/petroleum ether) showedcomplete reaction. The reaction flask was cooled to 0° C. and the excessAlH₃ was quenched by adding 25 ml of H₂ O/THF (1:2) dropwise followed by5 ml 1M NaOH. The mixture was transferred to a separatory funnel andextracted 3 times with ether. The ether extracts were combined, dried,concentrated and column chromatographed (5% ethyl acetate/petroleumether). The fractions containing product were rotary evaporated and theresulting oil was dissolved in 50 ml tetrahydrofuran and t-butanol. Tothis solution was added osmium tetroxide (2.5% in 2-methyl-2-propanol,5.1 ml) and N-methylmorpholine-N-oxide (2.7 g, 22.9 mmol), and themixture was stirred at RT for 18 h at which point 50 ml NAHCO₃ solutionwas added to neutralize any acid, the mixture transferred to aseparatory funnel and extracted 3 times with ethyl acetate. The organiclayers were washed with brine, dried (Na₂ SO₄) and concentrated. Columnchromatography (10% ethyl acetate/petroleum ether) yielded the product(3.41 g, 7.30 mmol, 75% yield). M.P.=107.5-110.0° C. ¹ H NMR (DMSO-d₆) δ7.42-6.81 (m, 7H); 3.90 (s, 3H); 3.65 (s, 2H); 3.31 (s, 2H); 1.51-0.97(m, 8H); 0.71 (m, 6H). MS Da/e=466, 468 (MH⁺). Calcd for C₂₂ H₂₈ BrNSO₃: C, 56.65; H, 6.05; N, 3.00; S, 6.87. Found: C, 56.80; H, 6.19; N,3.01; S, 6.80.

EXAMPLE 21

Preparation of(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide.

The compound of Example 20 (3.19 g, 6.84 mmol) was demethylated usingthe procedure for Example 18 giving the product (2.48 g, 77% yield).M.P=182.5-183.6° C. ¹ H NMR (DMSO-d₆) δ 10.87 (br s, 1H), 7.46-6.82 (m,7H), 3.62 (br s, 2H); 3.25 (s, 2H); 1.49-1.02 (m, 8H); 0.71 (m, 6H). MSDa/e=452, 454 (MH⁺). Calcd for C₂₁ H₂₆ BrNSO₃ : C, 55.75; H, 5.79; N,3.10; S, 7.09. Found: C, 55.79; H, 5.93; N, 3.15; S, 7.17.

EXAMPLE 22

Preparation of(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide.

To the compound of Example 21 (0.50 g, 1.10 mmol) in ethyl acetate (2.0ml) and sodium methoxide (10 ml, 25 wt %) was added copper(I) bromide(57 mg) and the mixture was refluxed for 2 h. The reaction mixture wasneutralized with 1N HCl and extracted with ether 3×15 ml. The etherextracts were dried and concentrated and the residue was applied to asilica gel column. The product was eluted with 20% ethylacetate/petroleum ether (0.44 g, 99% yield). ¹ H NMR (DMSO-d₆) δ 9.69(s, 1H), 7.26-6.52 (m, 7H); 3.60 (s, 5H); 1.53-1.02 (m, 8H); 0.71 (m,6H). MS Da/e=404 (MH⁺). Calcd for C₂₂ H₂₉ NSO₄ : C, 65.48; H, 7.24; N,3.47; S, 7.94. Found: C, 65.41; H, 7.26; N, 3.53; S, 8.02.

EXAMPLE 23

Preparation of(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide.

The compound of Example 20 (2.62 g, 5.62 mmol) was treated sodiummethoxide using the procedure for Example 22 to give the product (1.95g, 83% yield). ¹ H NMR (DMSO-d₆) δ 7.30 (s, 1H); 7.21-6.79 (m, 5H); 6.52(s, 1H); 3.80 (s, 3H); 3.62 (br s, 2H); 3.59 (s, 3H); 3.20 (s, 2H);1.53-0.98 (m, 8H); 0.73 (m, 6H). MS Da/e=418 (MH⁺). Calcd for C₂₃ H₃₁NSO₄ : C, 66.16; H, 7.48; N, 3.35; S, 7.68. Found: C, 66.10; H, 7.50; N,3.42; S, 7.74.

EXAMPLE 24

Preparation of(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol1,1-dioxide.

To sodium hydride (60%, 0.19 g, 4.79 mmol) in dimethylformamide (20 ml)was added ethanethiol (0.35 ml, 4.79 mmol) and the compound of Example23 (0.50 g, 1.19 mmol). The reaction mixture was refluxed for 3 h, then25 ml saturated ammnonium acetate (aq) was added, the pH adjusted to 7,and extracted with ethyl acetate 3×10 ml. The organic layer was dried,concentrated and applied to a silica gel column. The product was elutedwith 50% ethyl acetate/petroleum ether (0.40 g, 86% yield). ¹ H NMR(DMSO-d₆) δ 9.79 (br, 2H); 7.23 (s, 1H); 7.19-6.76 (m, 5H); 6.37 (s,1H); 3.58 (br s, 2H); 3.11 (s, 2H); 1.50-0.98 (m, 8H); 0.72 (m, 6H). MSDa/e=390 (MH⁺). Calcd for C₂₁ H₂₇ NSO₄ ×0.5 H₂ O: C, 63.29; H, 7.08; N,3.51; S, 8.05. Found: C, 63.47; H, 7.21; N, 3.36; S, 7.92.

EXAMPLE 25

Preparation of(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

(a)(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.

To a solution of the compound of Example 1(e) (8.28 g, 31.1 mmol) inacetic acid (30 ml) at RT was added dropwise bromine (1.75 ml, 34.2mmol) and stirred for 18 h. The reaction mixture was washed once withwater, extracted 2×20 ml ether, and the organic layer was dried,concentrated, and the residue loaded onto a silica gel column. Theproduct was eluted with 50% ethyl acetate/petroleum ether (9.23 g, 87%yield). M.P=104.4° C. ¹ H NMR (DMSO-d₆) δ 9.81 (s, 1H); 7.58 (s, 1H);7.42 (d, 1H); 7.04 (d, 1H); 2.96 (S, 2H); 1.73-1.40 (m, 4H); 1.19-1.15(m, 4H); 0.80 (t, 3H); 0.76 (t, 3H). MS Da/e=342, 344 (MH⁺). Calcd forC₁₅ H₂₀ BrNSO: C, 52.63; H, 5.89; N, 4.09; S, 9.37. Found: C, 52.76; H,5.93; N, 4.17; S, 9.21.

(b)(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one.

The compound of Example 25(a) (8.8 g, 23.61 mmol) was reacted withphenyl iodide according to the procedure used for Example 1(f) givingproduct (8.96 g, 91% yield) that is a 3:1 ratio of 7-bromide to 7-iodidethat can be coverted entirely to the 7-bromide by treatment with LiBr(10 eq) and copper (I) bromide (10 mol %) in refluxing DMF (18 h). ¹ HNMR (DMSO-d₆) δ 7.84 (d, 1H); 7.52 (dd, 1H); 7.37-7.03 (m, 5H); 6.84 (d,1H); 3.15 (S, 2H); 1.57-1.13 (m, 8H); 0.77 (m, 6H). MS Da/e=418, 420(MH⁺). Calcd for C₂₁ H₂₄ BrNSO: C, 60.29; H, 5.78, N, 3.35; Br, 19.10.Found: C, 60.56; H, 5.83; N, 3.25; Br, 18.83.

EXAMPLE 26

Preparation of(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide.

The compound of Example 25(b) (7.71 g, 18.4 mmol) was reacted with AlH₃using the procedure outlined for Example 3 providing an oil that wasdirectly treated with OsO₄ according to the procedure for Example 4. Theresulting sulfone was treated with sodium methoxide using the procedurefor Example 22 giving the product (67% yield overall for the threesteps). ¹ H NMR (DMSO-d₆) δ 7.35-6.79 (m, 8H); 3.79 (s, 3H); 3.62 (br s,2H); 3.26 (s, 2H); 1.53-1.00 (m, 8H); 0.73 (m, 6H). MS Da/e=388 (MH⁺).Calcd for C₂₂ H₂₉ NSO₃ : C, 68.18; H. 7.54; N, 3.61; S, 8.27. Found: C,67.89; H, 7.65; N, 3.42; S, 8.20.

EXAMPLE 27

Preparation of(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7-ol1,1-dioxide.

The compound of Example 26 (1.05 g, 2.71 mmol) was treated with aluminumbromide and ethanethiol according to the procedure for Example 18 givingthe title product (0.90 g, 89%). ¹ H NMR (DMSO-d₆) δ 9.99 (s, 1H);7.27-6.74 (m, 8H); 3.61 (br s, 2H), 3.20 (s, 2H); 1.50-1.00 (m, 8H);0.73 (m, 6H). MS Da/e=374 (MH⁺). Calcd for C₂₁ H₂₇ NSO₃ ×0.25 H₂ O: C,66.73; H, 7.33, N, 3.71, S, 8.48. Found: C, 66.67; H, 7.32; N, 3.67; S,8.49.

Biological Assay

In vivo inhibition of bile acid reabsorption

Male Spraque-Dawley rats (CD, Charles River) weighing 220-260 gm werehoused in individual cages and fed normal chow. The rats were dosed byoral gavage (1 ml/100 gm body weight) with test compounds as asuspension in 0.5% methylcellulose at 9:00 a.m. and 3:30 p.m. for twodays. The control group received 0.5% methylcellose. Two hours after themorning dose on day two, the rats were given a trace amount (1.3 nmoles)of 23,25-⁷⁵ Se-homocholic acid taurine (⁷⁵ SeHCAT) in 1.0 ml salineorally. ⁷⁵ SeHCAT, a synthetic gamma emitting bile acid analog which isabsorbed by the ileal bile acid active uptake system similar totaurocholic acid, has been used clinically as a measure of ileal bileacid absorption. Feces were collected over the 24 hours following ⁷⁵SeHCAT administration. Fecal content of ⁷⁵ SeHCAT was determined using aPackard Auto-Gamma 5000 Series gamma-counter. The % inhibition of bileacid reabsorption is calculated as follows: ##EQU1##

The percent of inhibition of bile acid reabsorption in the rat using ⁷⁵SeHCAT, for the compounds of Examples 2, 4, 7 and 9 at a concentrationof 10 mg/Kg was 7, 36, 20 and 29% respectively. In the same test, thecompounds of Examples 18, 22, 23, and 27 at a concentration of 1 mg/kggave between 50 and 65% inhibition of bile acid readsorption.

What is claimed is:
 1. The compounds of the formula (I) ##STR13##wherein R¹ and R² are the same or different and each is C₁₋₆ alkylgroup;R⁴ is a phenyl group optionally substituted with one to fivesubstituents which are the same or different and are each selected fromhalogen, hydroxy, nitro, phenyl-C₁₋₆ alkoxy, C₁₋₆ alkoxy, optionallysubstituted C₁₋₆ alkyl, S(O)_(n) R⁸, CO₂ R⁸, O(CH₂ CH₂ O)_(n) R⁸, OSO₂R⁸, O(CH₂)_(p) SO₃ R⁸, (CH₂)_(p) NR⁹ R¹⁰ and O(CH₂)_(p) N⁺ R⁹ R¹¹ R¹¹wherein R⁸ to R¹¹ are the same or different and are independentlyselected from hydrogen or optionally substituted C₁₋₆ alkyl, and whereinp is an integer from 1-4 and n is an integer from 0-3, and wherein saidoptionally substituted C₁₋₆ alkyl is optionally substituted withhydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, COR¹², nitrile, CO₂ R¹², SO₃R¹², NR¹³ R¹⁴ or N+R¹³ R¹⁴ R¹⁵ where R¹² to R¹⁵ are the same ordifferent and are selected from H and C₁₋₆ alkyl; R^(5a), R^(5b),R^(5c), and R^(5d) each represent atoms or groups which are the same ordifferent and each is hydrogen, C₁₋₄ alkoxy, halogen, hydroxy, or C₁₋₄alkyl optionally substituted by fluoro; R⁶ and R⁷ are the same ordifferent and each is hydrogen or a C₁₋₆ alkyl group; X is CH₂, C═O,C═S, or C═NR⁸ wherein R⁸ is as hereinbefore defined; and I is an integerfrom 0-2;and salts or solvates thereof.
 2. A compound of formula (I)according to claim I whereinR¹ is methyl or ethyl; R² is methyl, ethylor n-butyl; R⁴ is phenyl; R^(5a) and R^(5d) are hydrogen; R^(5b) andR^(5c) are the same or different and are each hydrogen, methyl, methoxy,hydroxy, trifluoromethyl or halo; R⁶ and R⁷ are the same or differentand are each hydrogen, methyl, ethyl or i-butyl; X is CH₂ or C═O; I is2;or a salt or solvate thereof.
 3. A compound of formula (I) which isselected from the group consistingof(±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;(±)-3-n-Butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;(±)-3-n-Butyl-2-isobutyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;3,3-Diethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one 1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;3,3-Dimethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one-1,1-dioxide;3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine;3,3-Dimethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol-1,1-dioxide;(±)-7-bromo-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;7-bromo-3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7,8-diol-1,1-dioxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7,8-diol-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1-monoxide;3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1-monoxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1-monoxide;3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol-1-monoxide;(±)-3-n-Butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine-1,1-dioxide;(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-8-methoxy-5-phenyl-1,5-benzothiazepin-4-one;(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,5-benzothiazepine 1,1-dioxide;(±)-7-Bromo-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide;(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide;(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide;(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepine-7,8-diol1,1-dioxide;(±)-7-Bromo-3-n-butyl-3-ethyl-2,3-dihydro-5-phenyl-1,5-benzothiazepin-4-one;(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepine1,1-dioxide; and(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,5-benzothiazepin-7-ol1,1-dioxide.
 4. A compound of formula (I) selectedfrom:(±)-3-n-butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,5-benzothiazepin-8-ol1,1-dioxide; and(±)-3-n-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-hydroxy-5-phenyl-1,5-benzothiazepine1,1-dioxideor a salt or solvate thereof.
 5. A method of treating aclinical condition in a mammal for which a bile acid uptake inhibitor isindicated which comprises, administering to a mammal an effective bileacid uptake inhibition amount of a compound of formula (I) according toclaim I or of a pharmaceutically acceptable salt or solvate thereof. 6.A method of treating a hyperlipidemic condition in a mammal whichcomprises, administering to the mammal an effective hyperlipidemictreatment amount of compound of formula (I) according to claim 1 or of apharmaceutically acceptable salt or solvate thereof.
 7. The method ofclaim 6 wherein the hyperlipidemic condition is atherosclerosis.
 8. Apharmaceutical composition comprising a compound of formula (I)according to claim 1 or a pharmaceutically acceptable salt or solvatethereof, and at least one pharmaceutically acceptable carrier.
 9. Aprocess for the manufacture of a compound of formula (I) according toclaim 1, or a salt or solvate thereof, which comprises:reacting acompound of formula (III) ##STR14## wherein R¹,R² and R^(5a),b,c,d areas hereinbefore defined, with the appropriate R⁴ -Z wherein R⁴ is ashereinbefore defined and Z is a suitable leaving group.
 10. The processaccording to claim 9, further comprising the steps:(i) when I is to be 1or 2, oxidation of the thio moiety; and/or (ii) when X is to be C═S,conversion of the C═O moiety; and/or (iii) when X is to be CH₂,reduction of the C═O moiety; and/or (iv) when R⁶ and/or R⁷ are to beother than hydrogen, reaction with the appropriate compound of formulaR⁶ -Z and/or R⁷ -Z wherein R⁶, R⁷, and Z are as hereinbefore defined,and/or (v) optional conversion of the resulting compound of formula(I)to a salt or solvate thereof, and/or (vi) optional resolution of anyoptical isomers of the compound of formula (I).
 11. The compound offormula (I) according to claim 1, wherein R¹ is ethyl and R² is n-butyl.12. The compound of formula (I) according to claim 1, wherein R⁴ isphenyl.
 13. The compound of formula (I) according to claim 1, whereinR^(5a) and R^(5d) are hydrogen, and R^(5b) and R^(5c) are the same ofdifferent and are each selected from the group consisting of hydrogen,methyl, methoxy, hydroxy, trifluoromethyl and halo.
 14. The compound offormula (I) according to claim 1, wherein R⁶ and R⁷ are both hydrogen.15. A process for the manufacture of a compound of formula (I) accordingto claim 1, or a salt or solvate thereof, where X is CH₂, said processcomprising reducing the carbonyl group of a compound of formula (II)##STR15## wherein R¹, R², R⁴, R^(5a), R^(5b), R^(5c), and R^(5d) are ashereinbefore defined.